Efficient process for the preparation of a factor Xa inhibitor

ABSTRACT

The present invention relates to the process for the preparation of the compound of Formula I:  
                 
 
     from its corresponding 3-cyano-4-fluorophenyl-pyrazole and intermediates useful therein.

FIELD OF THE INVENTION

[0001] This invention relates generally to an efficient process for thepreparation of a benzisoxazolyl-pyrazole. Benzisoxazolyl-pyrazoles areuseful as factor Xa inhibitors.

BACKGROUND OF THE INVENTION

[0002] Factor Xa inhibitors like those of Formula Ia shown below:

[0003] WO98/57951 describes the synthesis of the compound of Formula Ia,as its trifluoroacetic acid salt, as follows:

[0004] In the above procedure, the pyrazole carboxylic acid and anilineare coupled and isolated as a free base. The 3-cyano-4-fluorophenylgroup of the resulting product is then converted to1-aminobenzisoxazole. One problem with this procedure is that theacid-aniline coupling product is difficult to purify. A second problemis that the conversion to the 1-aminobenzisoxazole moiety requires thepresence of a strong, expensive base such as KOt-Bu.

[0005] It can be seen that the preparation of a compound of Formula I isdifficult. Thus, it is desirable to find an efficient synthesis of sucha compound.

SUMMARY OF THE INVENTION

[0006] Accordingly, one object of the present invention is to provide anovel process for preparing a compound of Formula I.

[0007] It is another object of the present invention to provideintermediates that are useful in preparing a compound of Formula I.

[0008] It is another object of the present invention to provide novelsalt, crystalline, and solvent forms of Formula I.

[0009] It is another object of the present invention to providepharmaceutical compositions comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of at least one of thecompounds of the present invention or a pharmaceutically acceptable saltthereof.

[0010] It is another object of the present invention to provide a methodfor treating thromboembolic disorders comprising administering to a hostin need of such treatment a therapeutically effective amount of at leastone of the compounds of the present invention or a pharmaceuticallyacceptable salt thereof.

[0011] It is another object of the present invention to provide novelcompounds for use in therapy.

[0012] It is another object of the present invention to provide the useof novel compounds for the manufacture of a medicament for the treatmentof a thromboembolic disorder.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0013] Thus, in an embodiment, the present invention provides a novelprocess for making a compound of Formula I:

[0014] comprising:

[0015] (c) contacting a compound of Formula IVa with maleic acid to forma compound of Formula IV;

[0016] (d) converting a compound of Formula IV to a compound of FormulaV; and,

[0017] (e) forming a compound of Formula I.

[0018] In a preferred embodiment, in (c), contacting with maleic acid isperformed in the presence of a first solvent, ethyl acetate.

[0019] In another preferred embodiment, in (c), a second solvent,1-chlorobutane, is added to enhance precipitation.

[0020] In another preferred embodiment, (d) is performed by contacting acompound of Formula IV with HONHCOCH₃ in the presence of a base and asolvent.

[0021] In another preferred embodiment, the base is selected from K₂CO₃,Na₂CO₃, KHCO₃, NaHCO₃, KF, NaOH, and KOH.

[0022] In another preferred embodiment, the base is K₂CO₃.

[0023] In another preferred embodiment, in (d), the solvent is selectedfrom DMSO, DMAC, N-methylpyrrolidinone, and DMF.

[0024] In another preferred embodiment, in (d), the solvent is DMF,comprising: 0.5 to 50% by volume of water.

[0025] In another preferred embodiment, in (d), the solvent is DMF,comprising: 10, 11, 12, 13, 14, to 15% by volume of water.

[0026] In another preferred embodiment, in (d), the solvent is DMF,comprising: 15% by volume of water.

[0027] In another preferred embodiment, (e) is performed by contacting acompound of Formula V with HCl in a solvent selected from methanol,acetonitrile, isopropyl alcohol, ethanol, propanol, acetone, methylisobutyl ketone (MIBK), 2-butanone, and water.

[0028] In another preferred embodiment, (e) is performed by contacting acompound of Formula V with HCl in ethanol.

[0029] In another preferred embodiment, the compound of Formula I is amono-HCl salt.

[0030] In another preferred embodiment, the compound of Formula I iscrystalline.

[0031] In another preferred embodiment, the compound of Formula I is asolvate selected from ethanol, propanol, isopropanol, acetone, MIBK,2-butanone, and water.

[0032] In a more preferred embodiment, the compound of Formula I is anethanol solvate.

[0033] In another embodiment, the present invention provides a novelprocess for making a compound of Formula IVa:

[0034] comprising:

[0035] (b) coupling compounds of Formulas II and III to form a compoundof Formula IVa.

[0036] In another preferred embodiment, the compound of Formula IVa isused without purification in (c).

[0037] In another preferred embodiment, (b) is performed by contacting acompound of Formula II with an acid activator, in a solvent and a firstbase, followed by contacting the resulting solution with a compound ofFormula III.

[0038] In another preferred embodiment, (b) is performed by contacting acompound of Formula II with oxalyl chloride in acetonitrile andpyridine, followed by contacting the resulting solution with a compoundof Formula III.

[0039] In another preferred embodiment, after a compound of Formula IIhas been contacted with a compound of Formula III, a second base isadded to the reaction solution.

[0040] In another preferred embodiment, the second base isdiisopropylethylamine.

[0041] In another embodiment, the present invention provides a novelprocess for making a compound of Formula II:

[0042] (a) contacting a compound of Formula VI with a compound ofFormula VII to form a compound of Formula VIII; and,

[0043] (a₁) converting a compound of Formula VIII to a compound ofFormula II.

[0044] In another embodiment, the present invention provides a novelcompound of Formula I:

[0045] wherein I is a mono-HCl salt.

[0046] In another preferred embodiment, the compound of Formula I iscrystalline.

[0047] In another preferred embodiment, the compound of Formula I is anethanol solvate.

[0048] In another embodiment, the present invention provides a novelcompound of Formula IV:

[0049] In another embodiment, the present invention provides a novelcompound of Formula Va:

[0050] or a pharmaceutically acceptable salt form thereof.

[0051] In another embodiment, the present invention provides novelpharmaceutical compositions, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of thepresent invention or a pharmaceutically acceptable salt form thereof.

[0052] In another embodiment, the present invention provides novelmethod for treating a thromboembolic disorder, comprising: administeringto a patient in need thereof a therapeutically effective amount of acompound of the present invention or a pharmaceutically acceptable saltform thereof.

[0053] In another embodiment, the present invention provides a compoundof the present invention for use in therapy.

[0054] In another embodiment, the present invention provides the use ofa compound of the present invention for the manufacture of a medicamentfor the treatment of a thromboembolic disorder.

DEFINITIONS

[0055] As used herein, the following terms and expressions have theindicated meanings. It will be appreciated that the compounds of thepresent invention may contain an asymmetrically substituted carbon atom,and may be isolated in optically active or racemic forms. It is wellknown in the art how to prepare optically active forms, such as byresolution of racemic forms or by synthesis from optically activestarting materials. All chiral, diastereomeric, and racemic forms andall geometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomer form is specifically indicated.

[0056] The processes of the present invention are contemplated to bepracticed on at least a multigram scale, kilogram scale, multikilogramscale, or industrial scale. Multigram scale, as used herein, ispreferably the scale wherein at least one starting material is presentin 10 grams or more, more preferably at least 50 grams or more, evenmore preferably at least 100 grams or more. Multikilogram scale, as usedherein, is intended to mean the scale wherein more than one kilogram ofat least one starting material is used. Industrial scale as used hereinis intended to mean a scale which is other than a laboratory scale andwhich is sufficient to supply product sufficient for either clinicaltests or distribution to consumers.

[0057] The term “substituted,” as used herein, means that any one ormore hydrogens on the designated atom are replaced with a selection fromthe indicated group, provided that the designated atom's normal valencyis not exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e.,=0), then 2 hydrogens on the atom arereplaced. Keto substituents are not present on aromatic moieties. When aring system (e.g., carbocyclic or heterocyclic) is said to besubstituted with a carbonyl group or a double bond, it is intended thatthe carbonyl group or double bond be part (i.e., within) of the ring.

[0058] The present invention is intended to include all isotopes ofatoms occurring in the present compounds. Isotopes include those atomshaving the same atomic number but different mass numbers. By way ofgeneral example and without limitation, isotopes of hydrogen includetritium and deuterium. Isotopes of carbon include C-13 and C-14.

[0059] The reactions of the synthetic methods claimed herein may bepreferably carried out in the presence of a base, the base being any ofa variety of bases, the presence of which in the reaction facilitatesthe synthesis of the desired product. Suitable bases may be selected byone of skill in the art of organic synthesis. Suitable bases include,but are not limited to, inorganic bases including, but not limited to,alkali metal, alkali earth metal, thallium, and ammonium hydroxides,alkoxides, phosphates, and carbonates, including, but not limited to,sodium hydroxide, potassium hydroxide, sodium carbonate, potassiumcarbonate, cesium carbonate, thallium hydroxide, thallium carbonate,tetra-n-butylammonium carbonate, and ammonium hydroxide.

[0060] The reactions of the synthetic methods claimed herein may becarried out in solvents that may be readily selected by one of skill inthe art of organic synthesis, the solvents generally are any one that issubstantially non-reactive with the starting materials (reactants),intermediates, or products at the temperatures at which the reactionsare carried out, i.e., temperatures which may range from the solvent'sfreezing temperature to the solvent's boiling temperature. A givenreaction may be carried out in one solvent or a mixture of more than onesolvent. Depending on the particular reaction step, suitable solventsfor a particular reaction step may be selected.

[0061] Suitable ether solvents include: dimethoxymethane,tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether,ethylene glycol dimethyl ether, ethylene glycol diethyl ether,diethylene glycol dimethyl ether, diethylene glycol diethyl ether,triethylene glycol dimethyl ether, or t-butyl methyl ether.

[0062] Suitable aprotic solvents may include, by way of example andwithout limitation, tetrahydrofuran (THF), dimethylformamide (DMF),dimethylacetamide (DMAC),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP),formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethylsulfoxide, propionitrile, ethyl formate, methyl acetate,hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate,sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane,nitrobenzene, or hexamethylphosphoramide.

[0063] The phrase “pharmaceutically acceptable” is employed herein torefer to those compounds, materials, compositions, and/or dosage formswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of human beings and animals withoutexcessive toxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

[0064] As used herein, “pharmaceutically acceptable salts” refer toderivatives of the disclosed compounds wherein the parent compound ismodified by making acid or base salts thereof. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic groups including, but not limitedto, amines, and alkali or organic salts of acidic groups including, butnot limited to, carboxylic acids. The pharmaceutically acceptable saltsinclude conventional non-toxic salts or quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, conventional non-toxic salts include those derivedfrom inorganic acids including, but not limited to, hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the saltsprepared from organic acids including, but not limited to, acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic.

[0065] The pharmaceutically acceptable salts of the present inventioncan be synthesized from the parent compound that contains a basic oracidic moiety by conventional chemical methods. Generally, salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileis preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

[0066] As used herein, “treating” or “treatment” cover the treatment ofa disease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting it development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

SYNTHESIS

[0067] The processes of the present invention can be practiced in anumber of ways depending on the solvent, base, and temperature chosen.As one of ordinary skill in the art of organic synthesis recognizes, thetime for reaction to run to completion as well as yield will bedependent upon all of the variables selected. The following schemes showa representation of the overall sequence of the present invention.

Preparation of Formula VIII

[0068]

[0069] VI can be converted to VIII by a novel hydrazine in-situ trappingprocedure. The hydrazine intermediate can be prepared by treating VIwith HCl and NaNO₂. Preferably, VI is added to a cooled (e.g., −10 to−5° C.) solution of HCl. The NaNO₂ can then added and the solutionpreferably maintained at a temperature of from 0-10° C. At this point,AcOH can be added to the solution. SnCl₂.2H₂O can then be added tocomplete formation of the hydrazine. The resulting product may beisolated or used in situ. Preferably, it is used in situ.

[0070] VIII can then be formed by addition of VII to the newly formedhydrazine. This addition is preferably performed in the presence of MeOHand at a temperature of from 35-55° C.

Preparation of Formula II

[0071]

[0072] Oxidation of VIII should provide II. The oxidation is performedby contacting VIII with an oxidant in the presence of a solvent andoptionally a buffer.

[0073] One of ordinary skill in the art would recognize that oxidantssuch as KMnO₄ or NaClO₂ can be used. Preferably, KMnO₄, in the presenceof a buffer, is used as the oxidant. VIII can be suspended in analcoholic solvent (e.g., t-butyl alcohol). The suspension is preferablymaintained at a temperature of from 35-50° C. An aqueous solution of abuffer known to those of skill in the art (e.g., monobasic sodiumphosphate monohydrate) can then be added. Preferably, the buffer isabout 0.5 to 4N. Aqueous KMnO₄ can then be added to the reactionsolution. After the reaction is complete, II can be isolated.

Preparation of Formula IVa

[0074]

[0075] IVa can be formed by coupling II and III. The coupling ispreferably performed by contacting II with an acid activator, in asolvent and in the presence of a base, followed by contacting theresulting solution with III. An acid activator like thionyl chloride oroxalyl chloride can be used, with oxalyl chloride being a preferredactivator. The addition of the acid activator is preferably performed ata temperature of from 10-30° C.

[0076] Contacting II and oxalyl chloride can be performed in a solventselected from acetonitrile, THF, and methylene chloride, withacetonitrile being preferred. The first base can be selected from DMAP,triethylamine, diisopropylethylamine, N-methyl morpholine, and pyridine,with pyridine being preferred. The amount of first base present ispreferably from 0.2 to 1 molar equivalent based on II, more preferablyit is 0.4 molar equivalents.

[0077] The desired amount of oxalyl chloride to be added will be basedon the amount of II present in the solution and the amount of waterpresent in the solution. The amount of water present can be determinedby known means, such as the Karl Fischer titration. Preferably, thenumber of moles of oxalyl chloride added is equal to or slightly greaterthan the sum of the number of moles of II and water present.

[0078] Once II has been activated, it can be contacted with III.Preferably, the reaction mixture is cooled to from 0-10° C. prior tocontacting with III. After contacting III with the reaction mixture, asecond base is preferably added. The second base can be selected fromdiisopropylethylamine, pyridine, DMAP, triethylamine, and N-methylmorpholine, with diisopropylethylamine being preferrred. The amount ofsecond base present is preferably from about 1-3 molar equivalents, morepreferably about 2.2 molar equivalents based on the amount of IIpresent.

Preparation of Formula IV

[0079]

[0080] IV can be formed from IVa with or without purification of IVa.Preferably, IV is formed from IVa without purification. IVa is usuallyisolated as an oily substance. IVa is preferably taken up in a firstsolvent and maleic acid is added. To this solution can be added a secondsolvent to enhance or accelerate precipitation of IV. Preferably from0.9 to 1.1 molar equivalents of maleic acid are present based on theamount of II present, more preferably about 0.95 molar equivalents. Thefirst solvent can be selected from the group acetone, chloroform, ethylacetate MIBK, i-propyl acetate, i-propyl alcohol, and THF, and ispreferably ethyl acetate. The second solvent can be selected from thegroup 1-chlorobutane, heptane, hexane, methylene chloride, and TBME, andis preferably 1-chlorobutane. Preferably, this reaction is run at aboutroom temperature.

Preparation of Formula V

[0081]

[0082] V can be prepared by contacting IV with HONHCOCH₃ in the presenceof a base and a solvent. Preferably, the base is selected from K₂CO₃,Na₂CO₃, KHCO₃, NaHCO₃, KF, NaOH, and KOH, with K₂CO₃ being a morepreferred base. The solvent may be selected from DMSO, dimethylformamide(DMF), dimethylacetamide (DMAC),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),1,3-dimethyl-2-imidazolidinone (DMI), and N-methylpyrrolidinone (NMP). Apreferred solvent is DMF. It is preferred that the DMF comprises 0.5 to50% by volume of water, more preferably, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, to 15% by volume of water, even more preferably 10,11, 12, 13, 14, to 15% by volume of water, and still more preferably 15%by volume of water.

[0083] Preferably, HONHCOCH₃, DMF, and K₂CO₃ are mixed together followedby contacting with water. This reaction mixture is preferably kept atabout 20-30° C. Upon contacting of the reaction mixture with IV, thereaction is preferably stirred at about room temperature.

Preparation of Formula I

[0084]

[0085] I can be formed from V by dissolving V in a solvent andcontacting this solution with HCl. Preferably, the solvent is selectedfrom methanol, acetonitrile, isopropyl alcohol, ethanol, propanol,acetone, methyl isobutyl ketone (MIBK), 2-butanone, and water, withethanol being a more preferred solvent. V is preferably taken up in asolvent (e.g., ethanol) at a temperature of from 60-80° C. HCl ispreferably contacted with the solution that is at a temperature of from20-40° C. Preferably, the HCl is in an alcoholic solution. The alcoholicsolution is preferably i-propyl alcohol.

[0086] I preferably precipitates from the reaction mixture. Thisprecipitation can be enhanced by cooling the mixture to a temperature ofabout 0-10° C. Preferably I is a crystalline mono-HCl salt. Morepreferably, I is a solvate selected from ethanol, propanol, isopropanol,acetone, MIBK, 2-butanone, and water. Even more preferably, I is anethanol solvate.

[0087] Other features of the invention will become apparent in thecourse of the following descriptions of exemplary embodiments that aregiven for illustration of the invention and are not intended to belimiting thereof.

EXAMPLES Example 1 Preparation of VIII

[0088] To a 40 L Hastelloy “C” reactor fitted with an overhead airstirrer, thermocouple, condenser and nitrogen inlet, was charged conc.HCl (5.5 L). The reactor was cooled to between −5 and −10° C. VI (tansolid, 726 g, 5.3 mol) was added over 12 minutes while maintaining theinternal temperature between −5 and −7° C. An additional 500 mL of conc.HCl was used to rinse down any VI hung up on the walls of the reactor.The resulting tan slurry was maintained at −5° C. over the next 10minutes while a solution of sodium nitrite (450 g, 6.5 mol) in 3.1 L ofpurified water was prepared. The first 1500 mL of the sodium nitritesolution was added over 20 minutes wherein the internal temperature roseto 10° C. The addition was stopped for 30 minutes in order for theinternal temperature to cool down and equilibrate to 2-3° C. Theaddition of sodium nitrite solution was resumed and the remaining 1.7 Lwas added over 30 minutes, while maintaining a temperature of 5-7° C.The batch was agitated for an additional 30 minutes at 6° C. Acetic acid(1.8 L) was added in one bolus with no appreciable change in theinternal temperature (6° C.). A solution of SnCl₂.2H₂O (2.8 kg, 12.2mol) was prepared in 1.9 L H₂O and 1.9 L of conc. HCl and added to thereaction over 55 minutes while maintaining the temperature between 6-10°C. The resulting white “milkshake-like” slurry was agitated for anadditional 30 minutes.

[0089] Methanol (10 L) was charged as one bolus into the reactor and thereaction mixture was heated to 40° C. A solution of4,4,4-trifluoro-2-furyl-1,3-butanedione (VII, 830 mL, 1.2 kg, 5.6 mol)in 3.1 L of MeOH was added over 35 minutes while maintaining an internaltemperature between 41-43° C. After addition was complete, the batch washeld between 45-50° C. for an additional 1.5 h whereupon the heat wasshut off and the resulting orange slurry was allowed to cool to ambienttemperature overnight (16 h) under a nitrogen atmosphere. The nextmorning, the batch was cooled further to help promote precipitation ofVIII. The batch was cooled down to 0° C. and held for 1 hour at 0° C.before dropping the slurry onto a Dacron filter cloth in a 32 cm Buchnerfunnel. The filtration took 1 hour and the cake depth was determined tobe 3.5 cm. The cake was rinsed with 3 L of cold (0-5° C.) 50/50isopropanol/water followed by 2.9 L of water. The wet cake (3.4 kg) wasdried to constant weight in a vacuum oven at 45° C. and 22 mm Hg overthe weekend to produce 1.3 Kg of VIII as a yellow solid (1.3 Kg, 94.5 wt%, 71.7% corrected yield).

Example 2 Preparation of II

[0090] A 50 L Hastelloy C reactor, equipped with an overhead airstirrer, a thermocouple, an addition funnel, a condenser, and a nitrogeninlet was charged with melted t-butyl alcohol (10 L), followed by solidVIII (1160 g). An additional quantity of t-butyl alcohol (4.5 L) wasused for purposes of rinsing the original containers and was added tothe reactor. The suspension was warmed to between 38° C. and 45° C.until a homogeneous solution resulted. An aqueous solution of monobasicsodium phosphate monohydrate (1245 g in 5.2 L of purified water) wasadded to the mixture over approx. 15 min between 35° C. and 45° C.Celite® 545 (3.2 Kg) was added to the reactor between 38° C. and 45° C.and stirring was maintained to insure even dispersion of the solid. Acommercial 40% aqueous solution of sodium permanganate (5.76 L) wasadded slowly over approx. 2.5 h, maintaining an internal temperaturerange between 42° C. and 50° C. The reaction mass was allowed to cool toambient temperature and was held overnight with continuous stirring.

[0091] The next morning, the mixture was again heated to between 45° C.and 50° C. and t-butyl methyl ether (6.0 L) was added, followed by solidCelite® 545 (3.2 Kg) and neutral alumina (4.15 Kg). The mixture wasstirred for approx. 15 min, filtered, and the cake was rinsed witht-butyl methyl ether (6 L total rinse volume). All filtrates obtainedwere recombined and the solvents were removed by distillation. When thedistillation had ceased, purified water (5 L) was added, followed by asecond distillation. The clear, homogeneous residue was diluted withwater to give 18 L of total solution. n-Chlorobutane (8 L) was added,the biphasic mixture was slowly stirred for 15 min, and the upper layerwas separated and discarded. The weakly basic aqueous layer was cooledto between 3° C. and 7° C. and 30% aqueous citric acid solution (3.3 L)was added, whereupon the crude II precipitated. The solids werecollected by filtration and the cake was rinsed with purified water (5.0L total rinse volume). Wet, yellow II was packed out and dried toconstant weight in a vacuum oven at 70° C., affording dry II (815.1 g;98.8 wt-%, 75% yield).

Example 3 Preparation of III

[0092] III can be prepared in accordance with the procedure described inco-pending U.S. Provisional Patent Application 60/220932, filed Jul. 26,2000, the contents of which are hereby incorporated by reference. Thefollowing is an example of the preparation of III.

[0093] Dimethylamine in THF (7.2 L of 2.0 M solution, 14.3 mol) wascharged into a 5 gallon Parr hydrogenator. 2-Formyl-imidazolyl (1.25 kg,13.0 mol) and methanol (2.4 L) was charged next. After pressure testingthe system with nitrogen, Pd/C (10%) (125 g, containing approximately50% by weight water) was charged. Jacket cooling was set at 25° C. Thebatch was then pressurized with hydrogen and the pressure was maintainedin the range 50-60 psig. The first 20 minutes of reaction saw a rise inthe internal temperature to 35° C. and hydrogen uptake was extremelyrapid. For the next 2 hours before the hydrogen pressure was released,the internal temperature was 30-31° C. HPLC analysis indicated that theconversion to 2-(N,N-dimethylaminomethyl)imidazole was complete(remaining 2-formyl-imidazolyl A% <2% versus2-(N,N-dimethylaminomethyl)imidazole >98%). The batch was filteredthrough a 0.5 micron cartridge filter and then through a 0.45 micronminifilter to remove Pd/C. A solution of 1/1 v/v MeOH/THF (5 L) was usedto wash out the reactor and line and was directed via the cartridgefilters to the carboy containing the rest of the filtrate. The combinedfiltrates were concentrated via rotary evaporator to a 2.3 kg solution(contained 1.6 Kg of 2-(N,N-dimethylaminomethyl)imidazole), which wasthen used directly for next step.

[0094] To each of two 22 L five neck round bottom flasks equipped withover head air stirrer, thermocouple, and distillation set-up withnitrogen cap was charged a solution of crude2-(N,N-dimethylaminomethyl)imidazole (4.86 kg of a solution made by theabove procedure that contained 3.0 Kg of2-(N,N-dimethylaminomethyl)imidazole). To each of the two reactors,anhydrous DMSO (10.0 L) was then introduced to give a dark amber clearsolution. The residual MeOH and THF from the crude2-(N,N-dimethylaminomethyl)imidazole in each of the two reactors wassubsequently distilled off in vacuo at 50-60° C. before 1-amino-2-fluoro-4-iodobenzene (2.15 Kg, 9.05 mole) and powdered K₂CO₃(2.5 Kg, 18.1 mole, 2.0 equiv) were added to each of the two reactors at40-50° C., respectively. Each of the two reactors was then degassedthree times with a vacuum/nitrogen cycle ending on nitrogen before beingcharged with powdered CuI (260 g, 1.35 mole, 0.15 equiv). The resultingreaction mixture in each of the two reactors was degassed three timesagain with a vacuum/nitrogen cycle ending on nitrogen before beingwarmed to 125-130° C.

[0095] When the reaction was deemed complete after 16 h at 125-130° C.(1- amino-2-fluoro-4-iodobenzene<5% at 254 nm via HPLC analysis), thereaction mixture in each of the two reactors was cooled to 40-50° C. Toeach of the two reactors was added 4.0 L of saturated NH₄Cl aqueoussolution, and the resulting mixture was agitated for 1 h at 20-25° C.The mixture was then filtered through a Celite® bed, and each of the tworeactors was washed with 1.0 L of saturated NH₄Cl aqueous solution and8.5 L of ethyl acetate. Half of the combined filtrates and washingsolution were sequentially poured into a 40 L reactor, and the mixturewas agitated at 20-25° C. for 0.5 h before the two layers wereseparated. The combined aqueous layers were poured back into the 40 Lreactor and were extracted with ethyl acetate (4×15 L). During theprocess of the organic solvent extraction, emulsion colloid was resolvedby filtration of the mixture through a Celite® bed before the two layerswere separated. The combined organic extracts were then washed with 6.0L of saturated NH₄Cl aqueous solution, dried over MgSO₄ (2.0 Kg), anddecolorized over active carbon (charcoal, 500 g) at 20-25° C. for 1 h intwo separate 22 L reactors. The mixture was filtered through a Celite®bed, and each of the reactors was washed with ethyl acetate (2 L). Thecombined organic filtrates were then poured into a 40 L reactor, and atotal of 68 L of ethyl acetate were successively distilled off in vacuoat 45-50° C. The residual slurry of the crude III in 9.0 L of ethylacetate was subsequently transferred into a 22 L reactor, and themixture was warmed to reflux (77-78° C.) to give a brown to blacksolution. Heptanes (6.0 L) were then added to the solution at 70° C.,and the solution was cooled to 45-50° C. before being treated withactive carbon (charcoal, 400 g). The mixture was warmed to reflux againfor 1 h before being filtered through a Celite® bed at 50-55° C. TheCelite® bed was washed with 2.0 L of ethyl acetate, and the combinedfiltrates and washing solution were poured back into a clean 22 Lreactor. A total of 5.0 L of ethyl acetate was distilled off in vacuo at45-50° C., and an additional 5.0 L of heptanes were added into thereactor at 50° C. The mixture was then gradually cooled to 20-25° C. andstirred at 20-25° C. for 1 h before being cooled to 5-10° C. for 2 h toprecipitate III. The solids were collected by filtration on a 27 cmporcelain funnel lined with Dacron® cloth and washed with 20% (v/v) ofTBME/heptanes (2×2.5 L). The solids were dried in vacuo with nitrogenpurge at 40-45° C. to a constant weight. The first crop of III (1.749Kg, 4.235 Kg theoretical, 41.3%) was obtained as pale-yellow crystals.

[0096] The combined mother liquor and washing solution was thenconcentrated in vacuo to afford the second crop of III (500 g, 4.235 kgtheoretical, 11.8%; a total of 53.1% yield) as pale-yellow crystals.

Example 4 Preparation of IVa and IV

[0097] II (781 g, 2.61 mol) was combined with acetonitrile (11.3 L). Theamount of water present in the solution was determined by performing aKarl Fischer titration. The volume of oxalyl chloride to be charged wascalculated by adding the moles of II plus moles of water determined tobe present to give moles of oxalyl chloride. Pyridine (81 mL, 1.0 mol)was charged followed by oxalyl chloride (227 mL, 2.60 mol). The reactionwas warmed to 55-60° C. and held at that temperature for 1 hour. Theprogress of the reaction was followed by drawing a sample and quenchinginto NH₄OH. Once the reaction was considered complete, a vacuumdistillation was performed to remove 12% (v/v) of the solvent. Followingthe distillation fresh acetonitrile was added back to the reaction toreplace the volume removed by the distillation.

[0098] The reaction mixture was chilled to 5° C. followed by theaddition of III (598 g, 2.55 mol). An exotherm of 12° C. accompanied theaddition. After allowing the solution to return to 5° C.,diisopropylethylamine (975 mL, 5.60 mol) was added to the reaction over60 minutes via addition funnel. Following the addition, the cooling bathwas removed and the reaction was allowed to return to room temperature.Two hours following the addition of base the reaction was complete. Thereaction was diluted with EtOAc (12 L) and washed with water (2×8 L).The aqueous washes were combined and back extracted with EtOAc (1×8 L).The organic fractions were combined and dried over MgSO₄, filtered andconcentrated to yield a brown oil, IVa.

[0099] The oil was reconstituted with EtOAc (11.3 L) and transferred toa 40 L kettle. Maleic acid (290 g, 2.50 mol) was added to the EtOAcsolution that was then stirred at room temperature for 60 minutes.Approximately 15 minutes after the addition of maleic acid the resultingsalt, IV, began to precipitate out of solution. 1-Chlorobutane (24 L)was added over 60-90 minutes to ensure complete precipitation. Followingthe addition of 1-chlorobutane, the IV solution was stirred at roomtemperature for 3 h. The salt was isolated by filtration and washed with1-chlorobutane (6 L). The solids were dried in a 75° C. vacuum oven toconstant weight to give 1.49 Kg (100.7 wt.%, 94.1% yield) of IV.

Example 5 Preparation of V

[0100] A 22 L reaction flask was charged with DMF (8 L), potassiumcarbonate (1576 g, 11.4 mol), and acetohydroxamic acid (428 g, 5.7 mol)and stirred at rt. Water (1.2 L, note: For Batch 1, 0.8 L of water wasfirst added and an additional 0.4 L of water was added after stirring atrt for 27 h) was added slowly while keeping the reaction temperature at20-30° C. After the reaction mixture was stirred for 30 min at 20-30°C., IV (1200 g, 1.9 mol) was added. The reaction mixture was stirred atrt for 4 to 20 h. This reaction mixture was quenched into 12 L of waterin a 40 L reactor with vigorous agitation. The resulting slurry wasstirred at rt for 2 h and then at 2-10° C. for another 1 h. The solidwas filtered with a Dacron filter cloth. The cake was washed with coldwater (8 L) and followed by cold acetonitrile (2 L) and dried in avacuum oven to constant weight to give a crude product (1012 g). Thecrude product was dissolved in 12.5 L of acetonitrile at 65-80° C. Afterthe solution was cooled to 25-37° C., water (2 L) was added over 2 hperiod while allowing the pot to cool to rt. The formed slurry wasstirred at rt for 1 h. After cooling to 2-10° C., the solid was filteredwith a Dacron filter cloth. The cake was washed with cold acetonitrile(4-6 L) and dried in a vacuum oven to constant weight to give theproduct V (92.3 g, 89%). HRMS for C₂₄H₂₁F₄O₂N₈ (M+H)⁺ calcd 529.1724,found 529.1722. ¹H-NMR (300 MHz, DMSO-d₆) 2.09 (6H), 3.29 (2H), 6.54(2H), 6.96 (1H), 7.41-7.75 (7H), 8.06 (1H), 10.65 (1H). ¹⁹F-NMR −119.632(1F), −61.257 (3F)

Example 6 Preparation of I

[0101] A 22 L reaction flask with overhead stirring, water condenser,and temperature probe was charged with ethanol (10 L) and V (monohydrateform, 850 g, 1.56 mol). The reaction mixture was heated to 65 to 80° C.to give a clear solution. After cooling to about 55° C., the warmsolution was filtered through a cartridge filter. After transferring thefiltrate back to the clean 22 L reactor and cooling the solution to20-37° C., 4.6N HCl in IPA solution (355 mL, 1.63 mol) was chargedthrough an addition funnel. After a slurry was formed, the mixture wasstirred at rt for 1 h, and then at 2-8° C. for another 1 h. The solidwas collected in a Buchner funnel with Dacron filter cloth. The cake waswashed with cold ethanol (2 L) and followed by tert-butyl methyl ether(6 L), dried in a vacuum oven at 50° C. to give the product I (858 g,98%). M.p. 258 C (dec). ¹H-NMR (300 MHz, DMSO-d₆) 1.02 (ethanol), 2.74(6H), 3.40 (ethanol), 4.35 (2H), 6.59(2H), 7.18 (1H), 7.34-7.80 (7H),8.09 (1H), 10.99 (1H). ¹⁹F-NMR −118.174 (1F), −61.229 (3F).

Example 7 Preparation of Va

[0102] To a solution of V (5.06 g) in chloroform (40 mL) and methanol(120 mL) was added 35% H₂O₂ (20 mL) at rt. The reaction mixture wasstirred at rt over 66 h. Water (180 mL) was then added to the reactionmixture and the resulting slurry was stirred at rt for 30 min. The solidwas collected by filtration and dried in vacuo with nitrogen purge at rtto a constant weight (3.97 g).

Utility

[0103] The novel compounds of the present invention are useful asanticoagulants for the treatment or prevention of thromboembolicdisorders in mammals. The term “thromboembolic disorders” as used hereinincludes arterial or venous cardiovascular or cerebrovascularthromboembolic disorders, including, for example, unstable angina, firstor recurrent myocardial infarction, ischemic sudden death, transientischemic attack, stroke, atherosclerosis, venous thrombosis, deep veinthrombosis, thrombophlebitis, arterial embolism, coronary and cerebralarterial thrombosis, cerebral embolism, kidney embolisms, and pulmonaryembolisms. The anticoagulant effect of compounds of the presentinvention is believed to be due to inhibition of factor Xa or thrombin.

[0104] The effectiveness of compounds of the present invention asinhibitors of factor Xa was determined using purified human factor Xaand synthetic substrate. The rate of factor Xa hydrolysis of chromogenicsubstrate S2222 (Kabi Pharmacia, Franklin, Ohio) was measured both inthe absence and presence of compounds of the present invention.Hydrolysis of the substrate resulted in the release of pNA, which wasmonitored spectrophotometrically by measuring the increase in absorbanceat 405 nM. A decrease in the rate of absorbance change at 405 nm in thepresence of inhibitor is indicative of enzyme inhibition. The results ofthis assay are expressed as inhibitory constant, K_(i).

[0105] Factor Xa determinations were made in 0.10 M sodium phosphatebuffer, pH 7.5, containing 0.20 M NaCl, and 0.5% PEG 8000. The Michaelisconstant, K_(m), for substrate hydrolysis was determined at 25° C. usingthe method of Lineweaver and Burk. Values of K_(i) were determined byallowing 0.2-0.5 nM human factor Xa (Enzyme Research Laboratories, SouthBend, Ind.) to react with the substrate (0.20 mM-1 mM) in the presenceof inhibitor. Reactions were allowed to go for 30 minutes and thevelocities (rate of absorbance change vs time) were measured in the timeframe of 25-30 minutes. The following relationship was used to calculateK_(i) values:

(v _(o) −v _(s))/v _(s) =I/(K _(i)(1+S/K _(m)))

[0106] where:

[0107] v_(o) is the velocity of the control in the absence of inhibitor;

[0108] v_(s) is the velocity in the presence of inhibitor;

[0109] I is the concentration of inhibitor;

[0110] K_(i) is the dissociation constant of the enzyme:inhibitorcomplex;

[0111] S is the concentration of substrate;

[0112] K_(m) is the Michaelis constant.

[0113] Compounds tested in the above assay are considered to be activeif they exhibit a K_(i) of ≦10 μM. Preferred compounds of the presentinvention have K_(i)'s of ≦1 μM. More preferred compounds of the presentinvention have K_(i)'s of ≦0.1 μM. Even more preferred compounds of thepresent invention have K_(i)'s of <0.01 μM. Still more preferredcompounds of the present invention have K_(i)'s of ≦0.001 μM. Using themethodology described above, a number of compounds of the presentinvention were found to exhibit a K_(i) of ≦10 μM, thereby confirmingthe utility of the compounds of the present invention as effective Xainhibitors.

[0114] The antithrombotic effect of compounds of the present inventioncan be demonstrated in a rabbit arterio-venous (AV) shunt thrombosismodel. In this model, rabbits weighing 2-3 kg anesthetized with amixture of xylazine (10 mg/kg i.m.) and ketamine (50 mg/kg i.m.) areused. A saline-filled AV shunt device is connected between the femoralarterial and the femoral venous cannulae. The AV shunt device consistsof a piece of 6-cm tygon tubing which contains a piece of silk thread.Blood will flow from the femoral artery via the AV-shunt into thefemoral vein. The exposure of flowing blood to a silk thread will inducethe formation of a significant thrombus. After forty minutes, the shuntis disconnected and the silk thread covered with thrombus is weighed.Test agents or vehicle will be given (i.v., i.p., s.c., or orally) priorto the opening of the AV shunt. The percentage inhibition of thrombusformation is determined for each treatment group. The ID50 values (dosewhich produces 50% inhibition of thrombus formation) are estimated bylinear regression.

[0115] The compounds of formula (I) may also be useful as inhibitors ofserine proteases, notably human thrombin, plasma kallikrein and plasmin.Because of their inhibitory action, these compounds are indicated foruse in the prevention or treatment of physiological reactions, bloodcoagulation and inflammation, catalyzed by the aforesaid class ofenzymes. Specifically, the compounds have utility as drugs for thetreatment of diseases arising from elevated thrombin activity such asmyocardial infarction, and as reagents used as anticoagulants in theprocessing of blood to plasma for diagnostic and other commercialpurposes.

[0116] Some compounds of the present invention were shown to be directacting inhibitors of the serine protease thrombin by their ability toinhibit the cleavage of small molecule substrates by thrombin in apurified system. In vitro inhibition constants were determined by themethod described by Kettner et al. in J. Biol. Chem. 265, 18289-18297(1990), herein incorporated by reference. In these assays,thrombin-mediated hydrolysis of the chromogenic substrate S2238 (HelenaLaboratories, Beaumont, Tex.) was monitored spectrophotometrically.Addition of an inhibitor to the assay mixture results in decreasedabsorbance and is indicative of thrombin inhibition. Human thrombin(Enzyme Research Laboratories, Inc., South Bend, Ind.) at aconcentration of 0.2 nM in 0.10 M sodium phosphate buffer, pH 7.5, 0.20M NaCl, and 0.5% PEG 6000, was incubated with various substrateconcentrations ranging from 0.20 to 0.02 mM. After 25 to 30 minutes ofincubation, thrombin activity was assayed by monitoring the rate ofincrease in absorbance at 405 nm which arises owing to substratehydrolysis. Inhibition constants were derived from reciprocal plots ofthe reaction velocity as a function of substrate concentration using thestandard method of Lineweaver and Burk. Using the methodology describedabove, some compounds of this invention were evaluated and found toexhibit a K_(i) of less than 15 μm, thereby confirming the utility ofthe compounds of the present invention as effective Xa inhibitors.

[0117] The compounds of the present invention can be administered aloneor in combination with one or more additional therapeutic agents. Theseinclude other anti-coagulant or coagulation inhibitory agents,anti-platelet or platelet inhibitory agents, thrombin inhibitors, orthrombolytic or fibrinolytic agents.

[0118] The compounds are administered to a mammal in a therapeuticallyeffective amount. By “therapeutically effective amount” it is meant anamount of a compound of Formula I that, when administered alone or incombination with an additional therapeutic agent to a mammal, iseffective to prevent or ameliorate the thromboembolic disease conditionor the progression of the disease.

[0119] By “administered in combination” or “combination therapy” it ismeant that the compound of Formula I and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect. Other anticoagulant agents (or coagulation inhibitory agents)that may be used in combination with the compounds of this inventioninclude warfarin and heparin, as well as other factor Xa inhibitors suchas those described in the publications identified above under Backgroundof the Invention.

[0120] The term anti-platelet agents (or platelet inhibitory agents), asused herein, denotes agents that inhibit platelet function such as byinhibiting the aggregation, adhesion or granular secretion of platelets.Such agents include, but are not limited to, the various knownnon-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin,ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam,diclofenac, sulfinpyrazone, and piroxicam, including pharmaceuticallyacceptable salts or prodrugs thereof. Of the NSAIDS, aspirin(acetylsalicyclic acid or ASA), and piroxicam are preferred. Othersuitable anti-platelet agents include ticlopidine, includingpharmaceutically acceptable salts or prodrugs thereof. Ticlopidine isalso a preferred compound since it is known to be gentle on thegastro-intestinal tract in use. Still other suitable platelet inhibitoryagents include IIb/IIIa antagonists, thromboxane-A2-receptor antagonistsand thromboxane-A2-synthetase inhibitors, as well as pharmaceuticallyacceptable salts or prodrugs thereof.

[0121] The term thrombin inhibitors (or anti-thrombin agents), as usedherein, denotes inhibitors of the serine protease thrombin. Byinhibiting thrombin, various thrombin-mediated processes, such asthrombin-mediated platelet activation (that is, for example, theaggregation of platelets, and/or the granular secretion of plasminogenactivator inhibitor-1 and/or serotonin) and/or fibrin formation aredisrupted. A number of thrombin inhibitors are known to one of skill inthe art and these inhibitors are contemplated to be used in combinationwith the present compounds. Such inhibitors include, but are not limitedto, boroarginine derivatives, boropeptides, heparins, hirudin andargatroban, including pharmaceutically acceptable salts and prodrugsthereof. Boroarginine derivatives and boropeptides include N-acetyl andpeptide derivatives of boronic acid, such as C-terminal a-aminoboronicacid derivatives of lysine, ornithine, arginine, homoarginine andcorresponding isothiouronium analogs thereof. The term hirudin, as usedherein, includes suitable derivatives or analogs of hirudin, referred toherein as hirulogs, such as disulfatohirudin. Boropeptide thrombininhibitors include compounds described in Kettner et al., U.S. Pat. No.5,187,157 and European Patent Application Publication Number 293 881 A2,the disclosures of which are hereby incorporated herein by reference.Other suitable boroarginine derivatives and boropeptide thrombininhibitors include those disclosed in PCT Application Publication Number92/07869 and European Patent Application Publication Number 471,651 A2,the disclosures of which are hereby incorporated herein by reference.

[0122] The term thrombolytics (or fibrinolytic) agents (or thrombolyticsor fibrinolytics), as used herein, denotes agents that lyse blood clots(thrombi). Such agents include tissue plasminogen activator,anistreplase, urokinase or streptokinase, including pharmaceuticallyacceptable salts or prodrugs thereof. The term anistreplase, as usedherein, refers to anisoylated plasminogen streptokinase activatorcomplex, as described, for example, in European Patent Application No.028,489, the disclosure of which is hereby incorporated herein byreference herein. The term urokinase, as used herein, is intended todenote both dual and single chain urokinase, the latter also beingreferred to herein as prourokinase.

[0123] Administration of the compounds of Formula I of the invention incombination with such additional therapeutic agent, may afford anefficacy advantage over the compounds and agents alone, and may do sowhile permitting the use of lower doses of each. A lower dosageminimizes the potential of side effects, thereby providing an increasedmargin of safety.

[0124] The compounds of the present invention are also useful asstandard or reference compounds, for example as a quality standard orcontrol, in tests or assays involving the inhibition of factor Xa. Suchcompounds may be provided in a commercial kit, for example, for use inpharmaceutical research involving factor Xa. For example, a compound ofthe present invention could be used as a reference in an assay tocompare its known activity to a compound with an unknown activity. Thiswould ensure the experimenter that the assay was being performedproperly and provide a basis for comparison, especially if the testcompound was a derivative of the reference compound. When developing newassays or protocols, compounds according to the present invention couldbe used to test their effectiveness.

[0125] The compounds of the present invention may also be used indiagnostic assays involving factor Xa. For example, the presence offactor Xa in an unknown sample could be determined by addition ofchromogenic substrate S2222 to a series of solutions containing testsample and optionally one of the compounds of the present invention. Ifproduction of pNA is observed in the solutions containing test sample,but no compound of the present invention, then one would conclude factorXa was present.

Dosage and Formulation

[0126] The compounds of this invention can be administered in such oraldosage forms as tablets, capsules (each of which includes sustainedrelease or timed release formulations), pills, powders, granules,elixirs, tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

[0127] The dosage regimen for the compounds of the present inventionwill, of course, vary depending upon known factors, such as thepharmacodynamic characteristics of the particular agent and its mode androute of administration; the species, age, sex, health, medicalcondition, and weight of the recipient; the nature and extent of thesymptoms; the kind of concurrent treatment; the frequency of treatment;the route of administration, the renal and hepatic function of thepatient,and the effect desired. A physician or veterinarian candetermine and prescribe the effective amount of the drug required toprevent, counter, or arrest the progress of the thromboembolic disorder.

[0128] By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will rangefrom about 1 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

[0129] Compounds of this invention can be administered in intranasalform via topical use of suitable intranasal vehicles, or via transdermalroutes, using transdermal skin patches. When administered in the form ofa transdermal delivery system, the dosage administration will, ofcourse, be continuous rather than intermittent throughout the dosageregimen.

[0130] The compounds are typically administered in admixture withsuitable pharmaceutical diluents, excipients, or carriers (collectivelyreferred to herein as pharmaceutical carriers) suitably selected withrespect to the intended form of administration, that is, oral tablets,capsules, elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

[0131] For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

[0132] The compounds of the present invention can also be administeredin the form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles, and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine, or phosphatidylcholines.

[0133] Compounds of the present invention may also be coupled withsoluble polymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

[0134] Dosage forms (pharmaceutical compositions) suitable foradministration may contain from about 1 milligram to about 100milligrams of active ingredient per dosage unit. In these pharmaceuticalcompositions the active ingredient will ordinarily be present in anamount of about 0.5-95% by weight based on the total weight of thecomposition.

[0135] Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

[0136] Liquid dosage forms for oral administration can contain coloringand flavoring to increase patient acceptance.

[0137] In general, water, a suitable oil, saline, aqueous dextrose(glucose), and related sugar solutions and glycols such as propyleneglycol or polyethylene glycols are suitable carriers for parenteralsolutions. Solutions for parenteral administration preferably contain awater soluble salt of the active ingredient, suitable stabilizingagents, and if necessary, buffer substances. Antioxidizing agents suchas sodium bisulfite, sodium sulfite, or ascorbic acid, either alone orcombined, are suitable stabilizing agents. Also used are citric acid andits salts and sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

[0138] Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

[0139] Representative useful pharmaceutical dosage-forms foradministration of the compounds of this invention can be illustrated asfollows:

Capsules

[0140] A large number of unit capsules can be prepared by fillingstandard two-piece hard gelatin capsules each with 100 milligrams ofpowdered active ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

[0141] A mixture of active ingredient in a digestable oil such assoybean oil, cottonseed oil or olive oil may be prepared and injected bymeans of a positive displacement pump into gelatin to form soft gelatincapsules containing 100 milligrams of the active ingredient. Thecapsules should be washed and dried.

Tablets

[0142] Tablets may be prepared by conventional procedures so that thedosage unit is 100 milligrams of active ingredient, 0.2 milligrams ofcolloidal silicon dioxide, 5 milligrams of magnesium stearate, 275milligrams of microcrystalline cellulose, 11 milligrams of starch and98.8 milligrams of lactose. Appropriate coatings may be applied toincrease palatability or delay absorption.

Injectable

[0143] A parenteral composition suitable for administration by injectionmay be prepared by stirring 1.5% by weight of active ingredient in 10%by volume propylene glycol and water. The solution should be madeisotonic with sodium chloride and sterilized.

Suspension

[0144] An aqueous suspension can be prepared for oral administration sothat each 5 mL contain 100 mg of finely divided active ingredient, 200mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mL of vanillin.

[0145] Where the compounds of this invention are combined with otheranticoagulant agents, for example, a daily dosage may be about 0.1 to100 milligrams of the compound of Formula I and about 1 to 7.5milligrams of the second anticoagulant, per kilogram of patient bodyweight. For a tablet dosage form, the compounds of this inventiongenerally may be present in an amount of about 5 to 10 milligrams perdosage unit, and the second anti-coagulant in an amount of about 1 to 5milligrams per dosage unit.

[0146] Where the compounds of Formula I are administered in combinationwith an anti-platelet agent, by way of general guidance, typically adaily dosage may be about 0.01 to 25 milligrams of the compound ofFormula I and about 50 to 150 milligrams of the anti-platelet agent,preferably about 0.1 to 1 milligrams of the compound of Formula I andabout 1 to 3 milligrams of antiplatelet agents, per kilogram of patientbody weight.

[0147] Where the compounds of Formula I are administered in combinationwith thrombolytic agent, typically a daily dosage may be about 0.1 to 1milligrams of the compound of Formula I, per kilogram of patient bodyweight and, in the case of the thrombolytic agents, the usual dosage ofthe thrombolyic agent when administered alone may be reduced by about70-80% when administered with a compound of Formula I.

[0148] Where two or more of the foregoing second therapeutic agents areadministered with the compound of Formula I, generally the amount ofeach component in a typical daily dosage and typical dosage form may bereduced relative to the usual dosage of the agent when administeredalone, in view of the additive or synergistic effect of the therapeuticagents when administered in combination.

[0149] Particularly when provided as a single dosage unit, the potentialexists for a chemical interaction between the combined activeingredients. For this reason, when the compound of Formula I and asecond therapeutic agent are combined in a single dosage unit they areformulated such that although the active ingredients are combined in asingle dosage unit, the physical contact between the active ingredientsis minimized (that is, reduced). For example, one active ingredient maybe enteric coated. By enteric coating one of the active ingredients, itis possible not only to minimize the contact between the combined activeingredients, but also, it is possible to control the release of one ofthese components in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial which effects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low-viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

[0150] These as well as other ways of minimizing contact between thecomponents of combination products of the present invention, whetheradministered in a single dosage form or administered in separate formsbut at the same time by the same manner, will be readily apparent tothose skilled in the art, once armed with the present disclosure.

[0151] Numerous modifications and variations of the present inventionare possible in light of the above teachings. It is therefore to beunderstood that within the scope of the appended claims, the inventionmay be practiced otherwise than as specifically described herein.

What is claimed is:
 1. A process for making a compound of Formula I:

comprising: (c) contacting a compound of Formula IVa with maleic acid toform a compound of Formula IV;

(d) converting a compound of Formula IV to a compound of Formula V; and,(e) forming a compound of Formula I.
 2. A process according to claim 1,wherein in (c), contacting with maleic acid is performed in the presenceof a first solvent, ethyl acetate.
 3. A process according to claim 2,wherein in (c), a second solvent, 1-chlorobutane, is added to enhanceprecipitation.
 4. A process according to claim 1, wherein (d) isperformed by contacting a compound of Formula IV with HONHCOCH₃ in thepresence of a base and a solvent.
 5. A process according to claim 4,wherein the base is selected from K₂CO₃, Na₂CO₃, KHCO₃, NaHCO₃, KF,NaOH, and KOH.
 6. A process according to claim 5, wherein the base isK₂CO₃.
 7. A process according to claim 4, wherein in (d), the solvent isselected from DMSO, DMAC, N-methylpyrrolidinone, and DMF.
 8. A processaccording to claim 7, wherein in (d), the solvent is DMF, comprising:0.5 to 50% by volume of water.
 9. A process according to claim 7,wherein in (d), the solvent is DMF, comprising: 10, 11, 12, 13, 14, to15% by volume of water.
 10. A process according to claim 7, wherein in(d), the solvent is DMF, comprising: 15% by volume of water.
 11. Aprocess according to claim 1, wherein (e) is performed by contacting acompound of Formula V with HCl in a solvent selected from methanol,acetonitrile, isopropyl alcohol, ethanol, propanol, acetone, methylisobutyl ketone (MIBK), 2-butanone, and water.
 12. A process accordingto claim 11, wherein (e) is performed by contacting a compound ofFormula V with HCl in ethanol.
 13. A process according to claim 1,wherein the compound of Formula I is a mono-HCl salt.
 14. A processaccording to claim 1, wherein the compound of Formula I is crystalline.15. A process according to claim 1, wherein the compound of Formula I isa solvate selected from ethanol, propanol, isopropanol, acetone, MIBK,2-butanone, and water.
 16. A process according to claim 15, wherein thecompound of Formula I is an ethanol solvate.
 17. A process according toclaim 1, wherein the compound of Formula IVa is prepared by the process,comprising:

(b) coupling compounds of Formulas II and III to form a compound ofFormula IVa.
 18. A process according to claim 17, wherein the compoundof Formula IVa is used without purification in (c).
 19. A processaccording to claim 17, wherein (b) is performed by contacting a compoundof Formula II with an acid activator, in a solvent and a first base,followed by contacting the resulting solution with a compound of FormulaIII.
 20. A process according to claim 19, wherein (b) is performed bycontacting a compound of Formula II with oxalyl chloride in acetonitrileand pyridine, followed by contacting the resulting solution with acompound of Formula III.
 21. A process according to claim 20, whereinafter a compound of Formula II has been contacted with a compound ofFormula III, a second base is added to the reaction solution.
 22. Aprocess according to claim 21, wherein the second base isdiisopropylethylamine.
 23. A process for making a compound of FormulaII:

comprising: (a) contacting a compound of Formula VI with a compound ofFormula VII to form a compound of Formula VIII; and, (a₁) converting acompound of Formula VIII to a compound of Formula II.
 24. A compound ofFormula I:

wherein I is a mono-HCl salt.
 25. A compound according to claim 24,wherein the compound of Formula I is crystalline.
 26. A compoundaccording to claim 24, wherein the compound of Formula I is a solvateselected from ethanol, propanol, isopropanol, acetone, MIBK, 2-butanone,and water.
 27. A compound according to claim 26, wherein the compound ofFormula I is an ethanol solvate.
 28. A compound of Formula IV:


29. A compound of Formula Va:

or a pharmaceutically acceptable salt form thereof.
 30. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound according to claim 24 ora pharmaceutically acceptable salt thereof.
 31. A method for treating athromboembolic disorder, comprising: administering to a patient in needthereof a therapeutically effective amount of a compound of claim 24 ora pharmaceutically acceptable salt thereof.